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McDougall SJ, Ong ZY, Heller R, Horton A, Thek KK, Choi EA, McNally GP, Lawrence AJ. Viscerosensory signalling to the nucleus accumbens via the solitary tract nucleus. J Neurochem 2024; 168:3116-3131. [PMID: 39032068 DOI: 10.1111/jnc.16180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 07/22/2024]
Abstract
The nucleus of the solitary tract (NTS) receives direct viscerosensory vagal afferent input that drives autonomic reflexes, neuroendocrine function and modulates behaviour. A subpopulation of NTS neurons project to the nucleus accumbens (NAc); however, the function of this NTS-NAc pathway remains unknown. A combination of neuroanatomical tracing, slice electrophysiology and fibre photometry was used in mice and/or rats to determine how NTS-NAc neurons fit within the viscerosensory network. NTS-NAc projection neurons are predominantly located in the medial and caudal portions of the NTS with 54 ± 7% (mice) and 65 ± 3% (rat) being TH-positive, representing the A2 NTS cell group. In horizontal brainstem slices, solitary tract (ST) stimulation evoked excitatory post-synaptic currents (EPSCs) in NTS-NAc projection neurons. The majority (75%) received low-jitter, zero-failure EPSCs characteristic of monosynaptic ST afferent input that identifies them as second order to primary sensory neurons. We then examined whether NTS-NAc neurons respond to cholecystokinin (CCK, 20 μg/kg ip) in vivo in both mice and rats. Surprisingly, there was no difference in the number of activated NTS-NAc cells between CCK and saline-treated mice. In rats, just 6% of NTS-NAc cells were recruited by CCK. As NTS TH neurons are the primary source for NAc noradrenaline, we measured noradrenaline release in the NAc and showed that NAc noradrenaline levels declined in response to cue-induced reward retrieval but not foot shock. Combined, these findings suggest that high-fidelity afferent information from viscerosensory afferents reaches the NAc. These signals are likely unrelated to CCK-sensitive vagal afferents but could interact with other sensory and higher order inputs to modulate learned appetitive behaviours.
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Affiliation(s)
- Stuart J McDougall
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Zhi Yi Ong
- School of Psychology, UNSW Sydney, Kensington, New South Wales, Australia
| | - Rosa Heller
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Anna Horton
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Kimberly K Thek
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Eun A Choi
- School of Psychology, UNSW Sydney, Kensington, New South Wales, Australia
| | - Gavan P McNally
- School of Psychology, UNSW Sydney, Kensington, New South Wales, Australia
| | - Andrew J Lawrence
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
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Neyens DM, Brenner L, Calkins R, Winzenried ET, Ritter RC, Appleyard SM. CCK-sensitive C fibers activate NTS leptin receptor-expressing neurons via NMDA receptors. Am J Physiol Regul Integr Comp Physiol 2024; 326:R383-R400. [PMID: 38105761 PMCID: PMC11381032 DOI: 10.1152/ajpregu.00238.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 12/07/2023] [Accepted: 12/07/2023] [Indexed: 12/19/2023]
Abstract
The hormone leptin reduces food intake through actions in the peripheral and central nervous systems, including in the hindbrain nucleus of the solitary tract (NTS). The NTS receives viscerosensory information via vagal afferents, including information from the gastrointestinal tract, which is then relayed to other central nervous system (CNS) sites critical for control of food intake. Leptin receptors (lepRs) are expressed by a subpopulation of NTS neurons, and knockdown of these receptors increases both food intake and body weight. Recently, we demonstrated that leptin increases vagal activation of lepR-expressing neurons via increased NMDA receptor (NMDAR) currents, thereby potentiating vagally evoked firing. Furthermore, chemogenetic activation of these neurons was recently shown to inhibit food intake. However, the vagal inputs these neurons receive had not been characterized. Here we performed whole cell recordings in brain slices taken from lepRCre × floxedTdTomato mice and found that lepR neurons of the NTS are directly activated by monosynaptic inputs from C-type afferents sensitive to the transient receptor potential vanilloid type 1 (TRPV1) agonist capsaicin. CCK administered onto NTS slices stimulated spontaneous glutamate release onto lepR neurons and induced action potential firing, an effect mediated by CCKR1. Interestingly, NMDAR activation contributed to the current carried by spontaneous excitatory postsynaptic currents (EPSCs) and enhanced CCK-induced firing. Peripheral CCK also increased c-fos expression in these neurons, suggesting they are activated by CCK-sensitive vagal afferents in vivo. Our results indicate that the majority of NTS lepR neurons receive direct inputs from CCK-sensitive C vagal-type afferents, with both peripheral and central CCK capable of activating these neurons and NMDARs able to potentiate these effects.
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Affiliation(s)
- Drew M Neyens
- Department of Integrated Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Lynne Brenner
- Department of Integrated Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Rowan Calkins
- Department of Integrated Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Eric T Winzenried
- Department of Integrated Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Robert C Ritter
- Department of Integrated Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
| | - Suzanne M Appleyard
- Department of Integrated Physiology and Neuroscience, Washington State University, Pullman, Washington, United States
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Ayoub M, Faris C, Tomanguillo J, Anwar N, Chela H, Daglilar E. The Use of Pre-Endoscopic Metoclopramide Does Not Prevent the Need for Repeat Endoscopy: A U.S. Based Retrospective Cohort Study. Life (Basel) 2024; 14:526. [PMID: 38672796 PMCID: PMC11051147 DOI: 10.3390/life14040526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/14/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Peptic ulcer disease (PUD) can cause upper gastrointestinal bleeding (UGIB), often needing esophagogastroduodenoscopy (EGD). Second-look endoscopies verify resolution, but cost concerns prompt research on metoclopramide's efficacy compared to erythromycin. METHODS We analyzed the Diamond Network of TriNetX Research database, dividing UGIB patients with PUD undergoing EGD into three groups: metoclopramide, erythromycin, and no medication. Using 1:1 propensity score matching, we compared repeat EGD, post-EGD transfusion, and mortality within one month in two study arms. RESULTS Out of 97,040 patients, 11.5% received metoclopramide, 3.9% received erythromycin, and 84.6% received no medication. Comparing metoclopramide to no medication showed no significant difference in repeat EGD (10.1% vs. 9.7%, p = 0.34), transfusion (0.78% vs. 0.86%, p = 0.5), or mortality (1.08% vs. 1.08%, p = 0.95). However, metoclopramide had a higher repeat EGD rate compared to erythromycin (9.4% vs. 7.5%, p = 0.003), with no significant difference in transfusion or mortality. CONCLUSIONS The need to repeat EGD was not decreased with pre-EGD use of metoclopramide. If a prokinetic agent is to be used prior to EGD, erythromycin shows superior reduction in the need of repeat EGD as compared to metoclopramide.
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Affiliation(s)
- Mark Ayoub
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Carol Faris
- Department of General Surgery, Marshall University, Huntington, WV 25755, USA;
| | - Julton Tomanguillo
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Nadeem Anwar
- Division of Gastroenterology and Hepatology, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Harleen Chela
- Division of Gastroenterology and Hepatology, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Ebubekir Daglilar
- Division of Gastroenterology and Hepatology, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
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Yang M, Wang JH, Shin JH, Lee D, Lee SN, Seo JG, Shin JH, Nam YD, Kim H, Sun X. Pharmaceutical efficacy of novel human-origin Faecalibacterium prausnitzii strains on high-fat-diet-induced obesity and associated metabolic disorders in mice. Front Endocrinol (Lausanne) 2023; 14:1220044. [PMID: 37711887 PMCID: PMC10497875 DOI: 10.3389/fendo.2023.1220044] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 08/04/2023] [Indexed: 09/16/2023] Open
Abstract
INTRODUCTION Obesity and related metabolic issues are a growing global health concern. Recently, the discovery of new probiotics with anti-obesity properties has gained interest. METHODS In this study, four Faecalibacte-rium prausnitzii strains were isolated from healthy human feces and evaluated on a high-fat diet-induced mouse model for 12 weeks. RESULTS The F. prausnitzii strains reduced body weight gain, liver and fat weights, and calorie intake while improving lipid and glucose metabolism in the liver and adipose tissue, as evidenced by regulating lipid metabolism-associated gene expression, including ACC1, FAS, SREBP1c, leptin, and adiponectin. Moreover, the F. prausnitzii strains inhibited low-grade inflammation, restored gut integrity, and ameliorated hepatic function and insulin resistance. Interestingly, the F. prausnitzii strains modulated gut and neural hormone secretion and reduced appetite by affecting the gut-brain axis. Supplementation with F. prausnitzii strains noticeably changed the gut microbiota composition. DISCUSSION In summary, the novel isolated F. prausnitzii strains have therapeutic effects on obesity and associated metabolic disorders through modulation of the gut-brain axis. Additionally, the effectiveness of different strains might not be achieved through identical mechanisms. Therefore, the present findings provide a reliable clue for developing novel therapeutic probiotics against obesity and associated metabolic disorders.
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Affiliation(s)
- Meng Yang
- Department of Nephrology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, Goyang-si, Republic of Korea
| | - Jing-Hua Wang
- Institute of Bioscience & Integrative Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Joo-Hyun Shin
- R&D Center, Enterobiome Inc., Goyang-si, Republic of Korea
| | - Dokyung Lee
- R&D Center, Enterobiome Inc., Goyang-si, Republic of Korea
| | - Sang-Nam Lee
- R&D Center, Enterobiome Inc., Goyang-si, Republic of Korea
| | - Jae-Gu Seo
- R&D Center, Enterobiome Inc., Goyang-si, Republic of Korea
| | - Ji-Hee Shin
- Research Group of Healthcare, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Young-Do Nam
- Research Group of Healthcare, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Hojun Kim
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, Goyang-si, Republic of Korea
| | - Xiaomin Sun
- Department of Nephrology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
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5
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Arabacı Tamer S, Yeğen BÇ. Peripheral administration of neuropeptide W inhibits gastric emptying in rats: The role of small diameter afferent fibers and cholecystokinin receptors. Neurosci Lett 2023; 800:137122. [PMID: 36775100 DOI: 10.1016/j.neulet.2023.137122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/08/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023]
Abstract
Neuropeptide W (NPW), a novel hypothalamic peptide, contributes to the central regulation of food intake and energy balance, and suppresses feeding behavior when administered centrally. The aim of our study was to investigate the role of peripherally administered NPW in the modulation of gastric emptying, and to evaluate the participation of afferent fibers, cholecystokinin (CCK) receptors and gastric smooth muscle contractility in the regulatory effects of NPW on gastric motility. In Sprague-Dawley male rats equipped with gastric fistula, gastric emptying rate of the saline and peptone solutions was measured following subcutaneous administration of NPW (0.1 or 5 μg/kg) preceded by subcutaneous injections of saline, CCK-1 or CCK-2 receptor antagonists. Another group of rats with cannulas were injected subcutaneously with capsaicin for afferent denervation before commencing emptying trials. The effect of NPW on carbachol-induced gastric contractility and the role of CCK receptors in gastric smooth muscle contractility were also assessed in gastric strips. Peripheral injection of NPW delayed gastric emptying rate of both caloric and non-caloric liquid test meals, while administration of CCK-1 or CCK-2 receptor antagonists or denervation of small diameter afferents reversed NPW-induced delay in gastric emptying. Moreover, NPW inhibited antrum contractility in the organ bath. Our results revealed that peripherally administered NPW delayed liquid emptying from the stomach via the involvement of small diameter afferent neurons and CCK receptors, and thereby this regulatory role may contribute to its central regulatory role in controlling food intake and energy balance.
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Affiliation(s)
- Sevil Arabacı Tamer
- Marmara University, School of Medicine, Department of Physiology, İstanbul, Turkey
| | - Berrak Ç Yeğen
- Marmara University, School of Medicine, Department of Physiology, İstanbul, Turkey.
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6
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von Gerichten J, Elnesr MH, Prollins JE, De Mel IA, Flanagan A, Johnston JD, Fielding BA, Short M. The [ 13 C]octanoic acid breath test for gastric emptying quantification: A focus on nutrition and modeling. Lipids 2022; 57:205-219. [PMID: 35799422 PMCID: PMC9546385 DOI: 10.1002/lipd.12352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 11/28/2022]
Abstract
Gastric emptying (GE) is the process of food being processed by the stomach and delivered to the small intestine where nutrients such as lipids are absorbed into the blood circulation. The combination of an easy and inexpensive method to measure GE such as the CO2 breath test using the stable isotope [13C]octanoic acid with semi‐mechanistic modeling could foster a wider application in nutritional studies to further understand the metabolic response to food. Here, we discuss the use of the [13C]octanoic acid breath test to label the solid phase of a meal, and the factors that influence GE to support mechanistic studies. Furthermore, we give an overview of existing mathematical models for the interpretation of the breath test data and how much nutritional studies could benefit from a physiological based pharmacokinetic model approach.
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Affiliation(s)
- Johanna von Gerichten
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Marwan H Elnesr
- Department of Chemical and Process Engineering, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, UK
| | - Joe E Prollins
- Department of Chemical and Process Engineering, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, UK
| | - Ishanki A De Mel
- Department of Chemical and Process Engineering, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, UK
| | - Alan Flanagan
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.,Section of Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Jonathan D Johnston
- Section of Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Barbara A Fielding
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Michael Short
- Department of Chemical and Process Engineering, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, UK
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7
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Hayes MR, Borner T, De Jonghe BC. The Role of GIP in the Regulation of GLP-1 Satiety and Nausea. Diabetes 2021; 70:1956-1961. [PMID: 34176783 PMCID: PMC8576421 DOI: 10.2337/dbi21-0004] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/01/2021] [Indexed: 11/18/2022]
Abstract
Gastric inhibitory peptide (GIP) is best known for its role as an incretin hormone in control of blood glucose concentrations. As a classic satiation signal, however, the literature illustrates a mixed picture of GIP involvement with an at best weak anorectic response profile being reported for GIP receptor (GIPR) signaling. Not surprisingly, the pursuit of exploiting the GIP system as a therapeutic target for diabetes and obesity has fallen behind that of the other gastrointestinal-derived incretin, glucagon-like peptide 1 (GLP-1). However, recent discoveries highlighted here support potential therapeutic advantages of combinatorial therapies targeting GIP and GLP-1 systems together, with perhaps the most surprising finding that GIPR agonism may have antiemetic properties. As nausea and vomiting are the most common side effects of all existing GLP-1 pharmacotherapies, the ability for GIP agonism to reduce GLP-1-induced illness behaviors but retain (if not enhance) weight loss and glycemic control may offer a new era in the treatment of obesity and diabetes.
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Affiliation(s)
- Matthew R Hayes
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
- Department of Biobehavioral Health Sciences, University of Pennsylvania, Philadelphia, PA
| | - Tito Borner
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
- Department of Biobehavioral Health Sciences, University of Pennsylvania, Philadelphia, PA
| | - Bart C De Jonghe
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
- Department of Biobehavioral Health Sciences, University of Pennsylvania, Philadelphia, PA
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8
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Hypothalamic detection of macronutrients via multiple gut-brain pathways. Cell Metab 2021; 33:676-687.e5. [PMID: 33450178 PMCID: PMC7933100 DOI: 10.1016/j.cmet.2020.12.018] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 10/30/2020] [Accepted: 12/23/2020] [Indexed: 12/24/2022]
Abstract
Food intake is tightly regulated by complex and coordinated gut-brain interactions. Nutrients rapidly modulate activity in key populations of hypothalamic neurons that regulate food intake, including hunger-sensitive agouti-related protein (AgRP)-expressing neurons. Because individual macronutrients engage specific receptors in the gut to communicate with the brain, we reasoned that macronutrients may utilize different pathways to reduce activity in AgRP neurons. Here, we revealed that AgRP neuron activity in hungry mice is inhibited by site-specific intestinal detection of different macronutrients. We showed that vagal gut-brain signaling is required for AgRP neuron inhibition by fat. In contrast, spinal gut-brain signaling relays the presence of intestinal glucose. Further, we identified glucose sensors in the intestine and hepatic portal vein that mediate glucose-dependent AgRP neuron inhibition. Therefore, distinct pathways are activated by individual macronutrients to inhibit AgRP neuron activity.
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9
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Kumar U, Singh S. Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity. Int J Mol Sci 2020; 21:ijms21072568. [PMID: 32272767 PMCID: PMC7177963 DOI: 10.3390/ijms21072568] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/29/2020] [Accepted: 04/02/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is one of the major social and health problems globally and often associated with various other pathological conditions. In addition to unregulated eating behaviour, circulating peptide-mediated hormonal secretion and signaling pathways play a critical role in food intake induced obesity. Amongst the many peptides involved in the regulation of food-seeking behaviour, somatostatin (SST) is the one which plays a determinant role in the complex process of appetite. SST is involved in the regulation of release and secretion of other peptides, neuronal integrity, and hormonal regulation. Based on past and recent studies, SST might serve as a bridge between central and peripheral tissues with a significant impact on obesity-associated with food intake behaviour and energy expenditure. Here, we present a comprehensive review describing the role of SST in the modulation of multiple central and peripheral signaling molecules. In addition, we highlight recent progress and contribution of SST and its receptors in food-seeking behaviour, obesity (orexigenic), and satiety (anorexigenic) associated pathways and mechanism.
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10
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Meister AL, Jiang Y, Doheny KK, Travagli RA. Correlation between the motility of the proximal antrum and the high-frequency power of heart rate variability in freely moving rats. Neurogastroenterol Motil 2019; 31:e13633. [PMID: 31119854 PMCID: PMC6639127 DOI: 10.1111/nmo.13633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 04/18/2019] [Accepted: 05/08/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Cardiac vagal tone can be monitored non-invasively via electrocardiogram measurements of the high-frequency power spectrum of heart rate variability (HF-HRV). Vagal inputs to the upper GI tract are cumbersome to measure non-invasively. Although cardiac and GI vagal outputs arise from distinct brainstem nuclei, the nucleus ambiguus, and the dorsal motor nucleus of the vagus, respectively, we aim to test the hypotheses that in freely moving rats HF-HRV power is correlated to proximal antral motility and can be altered by high levels of circulating estrogen and vagal-selective treatments known to affect antral motility. METHODS Male and female Sprague-Dawley rats were implanted with a miniaturized strain gauge on the proximal gastric antrum and ECG electrodes to collect simultaneous antral motility and electrocardiogram. After recovery, male rats underwent baseline recordings before and after administration of saline (N = 8), cholecystokinin (CCK; N = 7), ghrelin (N = 6), or food (N = 6). Female rats (N = 6) underwent twice-daily recordings to determine baseline correlations during estrous cycle stages. KEY RESULTS There was a significant positive correlation between HF-HRV and proximal antral motility at baseline in males and females with low, but not high, estrogen levels. In male rats, the significant positive correlation was maintained following CCK, but not ghrelin or food administration. CONCLUSIONS AND INFERENCES Our data suggest that in rodents, HF-HRV positively correlates to proximal antral motility at baseline conditions in males and low-estrogen females or following interventions, such as CCK, known to affect vagal tone. This correlation is not observed when antral motility is influenced by more complex events.
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Affiliation(s)
- Alissa L. Meister
- Neural and Behavioral Sciences, Penn State College of Medicine, Hershey PA
| | - Yanyan Jiang
- Neural and Behavioral Sciences, Penn State College of Medicine, Hershey PA
| | - Kim K. Doheny
- Neural and Behavioral Sciences, Penn State College of Medicine, Hershey PA,Division of Neonatal-Perinatal Medicine, Penn State College of Medicine, Hershey PA
| | - R. Alberto Travagli
- Neural and Behavioral Sciences, Penn State College of Medicine, Hershey PA,Corresponding author: Dr. R. Alberto Travagli, Department of Neural and Behavioral Sciences, Penn State College of Medicine, 500 University Drive, MC H109, Hershey, PA 17033,
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11
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Goyal RK, Guo Y, Mashimo H. Advances in the physiology of gastric emptying. Neurogastroenterol Motil 2019; 31:e13546. [PMID: 30740834 PMCID: PMC6850045 DOI: 10.1111/nmo.13546] [Citation(s) in RCA: 197] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/29/2018] [Accepted: 12/16/2018] [Indexed: 12/16/2022]
Abstract
There have been many recent advances in the understanding of various aspects of the physiology of gastric motility and gastric emptying. Earlier studies had discovered the remarkable ability of the stomach to regulate the timing and rate of emptying of ingested food constituents and the underlying motor activity. Recent studies have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric inhibition and excitation and therefore the rate of gastric emptying. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neurons in the DMV and postganglionic excitatory cholinergic neurons in the myenteric plexus. Smooth muscle is the final target of these circuits. The role of the intramuscular interstitial cells of Cajal in neuromuscular transmission remains debatable. The two motor circuits are differentially regulated by different sets of neurons in the NTS and vagal afferents. In the digestive period, many hormones including cholecystokinin and GLP-1 inhibit gastric emptying via the GIVMC, and in the inter-digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulating the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and orexigenic neural pathways, respectively. Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.
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Affiliation(s)
- Raj K. Goyal
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
| | - Yanmei Guo
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
| | - Hiroshi Mashimo
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
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12
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Page SJ, Zhu M, Appleyard SM. Effects of acute and chronic nicotine on catecholamine neurons of the nucleus of the solitary tract. Am J Physiol Regul Integr Comp Physiol 2018; 316:R38-R49. [PMID: 30354182 DOI: 10.1152/ajpregu.00344.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nicotine is an addictive drug that has broad effects throughout the brain. One site of action is the nucleus of the solitary tract (NTS), where nicotine initiates a stress response and modulates cardiovascular and gastric function through nicotinic acetylcholine receptors (nAChRs). Catecholamine (CA) neurons in the NTS influence stress and gastric and cardiovascular reflexes, making them potential mediators of nicotine's effects; however nicotine's effect on these neurons is unknown. Here, we determined nicotine's actions on NTS-CA neurons by use of patch-clamp techniques in brain slices from transgenic mice expressing enhanced green fluorescent protein driven by the tyrosine hydroxylase promoter (TH-EGFP). Picospritzing nicotine both induced a direct inward current and increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in NTS-CA neurons, effects blocked by nonselective nAChR antagonists TMPH and MLA. The increase in sEPSC frequency was mimicked by nAChRα7 agonist AR-R17779 and blocked by nAChRα7 antagonist MG624. AR-R17779 also increased the firing of TH-EGFP neurons, an effect dependent on glutamate inputs, as it was blocked by the glutamate antagonist NBQX. In contrast, the nicotine-induced current was mimicked by nAChRα4β2 agonist RJR2403 and blocked by nAChRα4β2 antagonist DHβE. RJR2403 also increased the firing rate of TH-EGFP neurons independently of glutamate. Finally, both somatodendritic and sEPSC nicotine responses from NTS-CA neurons were larger in nicotine-dependent mice that had under gone spontaneous nicotine withdrawal. These results demonstrate that 1) nicotine activates NTS-CA neurons both directly, by inducing a direct current, and indirectly, by increasing glutamate inputs, and 2) NTS-CA nicotine responsiveness is altered during nicotine withdrawal.
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Affiliation(s)
- Stephen J Page
- Program in Neuroscience, Department of Integrative Physiology and Neuroscience, Washington State University , Pullman, Washington
| | - Mingyan Zhu
- Program in Neuroscience, Department of Integrative Physiology and Neuroscience, Washington State University , Pullman, Washington
| | - Suzanne M Appleyard
- Program in Neuroscience, Department of Integrative Physiology and Neuroscience, Washington State University , Pullman, Washington
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Udit S, Burton M, Rutkowski JM, Lee S, Bookout AL, Scherer PE, Elmquist JK, Gautron L. Na v1.8 neurons are involved in limiting acute phase responses to dietary fat. Mol Metab 2017; 6:1081-1091. [PMID: 29031710 PMCID: PMC5641637 DOI: 10.1016/j.molmet.2017.07.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 07/19/2017] [Accepted: 07/24/2017] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE AND METHODS Metabolic viscera and their vasculature are richly innervated by peripheral sensory neurons. Here, we examined the metabolic and inflammatory profiles of mice with selective ablation of all Nav1.8-expressing primary afferent neurons. RESULTS While mice lacking sensory neurons displayed no differences in body weight, food intake, energy expenditure, or body composition compared to controls on chow diet, ablated mice developed an exaggerated inflammatory response to high-fat feeding characterized by bouts of weight loss, splenomegaly, elevated circulating interleukin-6 and hepatic serum amyloid A expression. This phenotype appeared to be directly mediated by the ingestion of saturated lipids. CONCLUSIONS These data demonstrate that the Nav1.8-expressing afferent neurons are not essential for energy balance but are required for limiting the acute phase response caused by an obesogenic diet.
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Affiliation(s)
- Swalpa Udit
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Michael Burton
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Joseph M Rutkowski
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Syann Lee
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Angie L Bookout
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Joel K Elmquist
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA.
| | - Laurent Gautron
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA.
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Carbon dioxide in carbonated beverages induces ghrelin release and increased food consumption in male rats: Implications on the onset of obesity. Obes Res Clin Pract 2017; 11:534-543. [PMID: 28228348 DOI: 10.1016/j.orcp.2017.02.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 01/15/2017] [Accepted: 02/02/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND The dangerous health risks associated with obesity makes it a very serious public health issue. Numerous studies verified a correlation between the increase in obesity and the parallel increase in soft drink consumption among world populations. The effects of one main component in soft drinks namely the carbon dioxide gas has not been studied thoroughly in any previous research. METHODS Male rats were subjected to different categories of drinks and evaluated for over a year. Stomach ex vivo experiments were undertaken to evaluate the amount of ghrelin upon different beverage treatments. Moreover, 20 male students were tested for their ghrelin levels after ingestion of different beverages. RESULTS Here, we show that rats consuming gaseous beverages over a period of around 1 year gain weight at a faster rate than controls on regular degassed carbonated beverage or tap water. This is due to elevated levels of the hunger hormone ghrelin and thus greater food intake in rats drinking carbonated drinks compared to control rats. Moreover, an increase in liver lipid accumulation of rats treated with gaseous drinks is shown opposed to control rats treated with degassed beverage or tap water. In a parallel study, the levels of ghrelin hormone were increased in 20 healthy human males upon drinking carbonated beverages compared to controls. CONCLUSIONS These results implicate a major role for carbon dioxide gas in soft drinks in inducing weight gain and the onset of obesity via ghrelin release and stimulation of the hunger response in male mammals.
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Tan C, Wei H, Zhao X, Xu C, Zhou Y, Peng J. Soluble Fiber with High Water-Binding Capacity, Swelling Capacity, and Fermentability Reduces Food Intake by Promoting Satiety Rather Than Satiation in Rats. Nutrients 2016; 8:nu8100615. [PMID: 27706095 PMCID: PMC5084003 DOI: 10.3390/nu8100615] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 09/20/2016] [Accepted: 09/26/2016] [Indexed: 01/10/2023] Open
Abstract
To understand whether soluble fiber (SF) with high water-binding capacity (WBC), swelling capacity (SC) and fermentability reduces food intake and whether it does so by promoting satiety or satiation or both, we investigated the effects of different SFs with these properties on the food intake in rats. Thirty-two male Sprague-Dawley rats were randomized to four equal groups and fed the control diet or diet containing 2% konjac flour (KF), pregelatinized waxy maize starch (PWMS) plus guar gum (PG), and PWMS starch plus xanthan gum (PX) for three weeks, with the measured values of SF, WBC, and SC in the four diets following the order of PG > KF > PX > control. Food intake, body weight, meal pattern, behavioral satiety sequence, and short-chain fatty acids (SCFAs) in cecal content were evaluated. KF and PG groups reduced the food intake, mainly due to the decreased feeding behavior and increased satiety, as indicated by decreased meal numbers and increased inter-meal intervals. Additionally, KF and PG groups increased concentrations of acetate acid, propionate acid, and SCFAs in the cecal contents. Our results indicate that SF with high WBC, SC, and fermentability reduces food intake—probably by promoting a feeling of satiety in rats to decrease their feeding behavior.
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Affiliation(s)
- Chengquan Tan
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Xichen Zhao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Chuanhui Xu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Yuanfei Zhou
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
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Camilleri M. Peripheral mechanisms in appetite regulation. Gastroenterology 2015; 148:1219-33. [PMID: 25241326 PMCID: PMC4369188 DOI: 10.1053/j.gastro.2014.09.016] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 09/09/2014] [Accepted: 09/15/2014] [Indexed: 12/13/2022]
Abstract
Peripheral mechanisms in appetite regulation include the motor functions of the stomach, such as the rate of emptying and accommodation, which convey symptoms of satiation to the brain. The rich repertoire of peripherally released peptides and hormones provides feedback from the arrival of nutrients in different regions of the gut from where they are released to exert effects on satiation, or regulate metabolism through their incretin effects. Ultimately, these peripheral factors provide input to the highly organized hypothalamic circuitry and vagal complex of nuclei to determine cessation of energy intake during meal ingestion, and the return of appetite and hunger after fasting. Understanding these mechanisms is key to the physiological control of feeding and the derangements that occur in obesity and their restoration with treatment (as shown by the effects of bariatric surgery).
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
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Zhao H, Peters JH, Zhu M, Page SJ, Ritter RC, Appleyard SM. Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract. J Physiol 2014; 593:111-25. [PMID: 25281729 DOI: 10.1113/jphysiol.2013.258103] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 09/15/2014] [Indexed: 12/28/2022] Open
Abstract
Hindbrain NMDA receptors play important roles in reflexive and behavioural responses to vagal activation. NMDA receptors have also been shown to contribute to the synaptic responses of neurons in the nucleus of the solitary tract (NTS), but their exact role remains unclear. In this study we used whole cell patch-clamping techniques in rat horizontal brain slice to investigate the role of NMDA receptors in the fidelity of transmission across solitary tract afferent-NTS neuron synapses. Results show that NMDA receptors contribute up to 70% of the charge transferred across the synapse at high (>5 Hz) firing rates, but have little contribution at lower firing frequencies. Results also show that NMDA receptors critically contribute to the fidelity of transmission across these synapses during high frequency (>5 Hz) afferent discharge rates. This novel role of NMDA receptors may explain in part how primary visceral afferents, including vagal afferents, can maintain fidelity of transmission across a broad range of firing frequencies. Neurons within the nucleus of the solitary tract (NTS) receive vagal afferent innervations that initiate gastrointestinal and cardiovascular reflexes. Glutamate is the fast excitatory neurotransmitter released in the NTS by vagal afferents, which arrive there via the solitary tract (ST). ST stimulation elicits excitatory postsynaptic currents (EPSCs) in NTS neurons mediated by both AMPA- and NMDA-type glutamate receptors (-Rs). Vagal afferents exhibit a high probability of vesicle release and exhibit robust frequency-dependent depression due to presynaptic vesicle depletion. Nonetheless, synaptic throughput is maintained even at high frequencies of afferent activation. Here we test the hypothesis that postsynaptic NMDA-Rs are essential in maintaining throughput across ST-NTS synapses. Using patch clamp electrophysiology in horizontal brainstem slices, we found that NMDA-Rs, including NR2B subtypes, carry up to 70% of the charge transferred across the synapse during high frequency stimulations (>5 Hz). In contrast, their relative contribution to the ST-EPSC is much less during low (<2 Hz) frequency stimulations. Afferent-driven activation of NMDA-Rs produces a sustained depolarization during high, but not low, frequencies of stimulation as a result of relatively slow decay kinetics. Hence, NMDA-Rs are critical for maintaining action potential generation at high firing rates. These results demonstrate a novel role for NMDA-Rs enabling a high probability of release synapse to maintain the fidelity of synaptic transmission during high frequency firing when glutamate release and AMPA-R responses are reduced. They also suggest why NMDA-Rs are critical for responses that may depend on high rates of afferent discharge.
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Affiliation(s)
- Huan Zhao
- Program in Neuroscience, Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, 99164, USA
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Romano A, Karimian Azari E, Tempesta B, Mansouri A, Micioni Di Bonaventura MV, Ramachandran D, Lutz TA, Bedse G, Langhans W, Gaetani S. High dietary fat intake influences the activation of specific hindbrain and hypothalamic nuclei by the satiety factor oleoylethanolamide. Physiol Behav 2014; 136:55-62. [PMID: 24802360 DOI: 10.1016/j.physbeh.2014.04.039] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 04/23/2014] [Accepted: 04/27/2014] [Indexed: 12/16/2022]
Abstract
Chronic exposure to a diet rich in fats changes the gastrointestinal milieu and alters responses to several signals involved in the control of food intake. Oleoylethanolamide (OEA) is a gut-derived satiety signal released from enterocytes upon the ingestion of dietary fats. The anorexigenic effect of OEA, which requires intestinal PPAR-alpha receptors and is supposedly mediated by vagal afferents, is associated with the induction of c-fos in several brain areas involved in the control of food intake, such as the nucleus of the solitary tract (NST) and the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). In the present study we investigated whether the exposure to a high fat diet (HFD) alters the hindbrain and hypothalamic responses to OEA. To this purpose we evaluated the effects of OEA at a dose that reliably inhibits eating (10mg/kg i.p.) on the induction of c-fos in the NST, area postrema (AP), PVN and SON in rats maintained either on standard chow or a HFD. We performed a detailed analysis of the different NST subnuclei activated by i.p. OEA and found that peripheral OEA strongly activates c-fos expression in the AP, NST and in the hypothalamus of both chow and HFD fed rats. The extent of c-fos expression was, however, markedly different between the two groups of rats, with a weaker activation of selected NST subnuclei and stronger activation of the PVN in HFD-fed than in chow-fed rats. HFD-fed rats were also more sensitive to the immediate hypophagic action of OEA than chow-fed rats. These effects may be due to a decreased sensitivity of vagal afferent fibers that might mediate OEA's actions on the brain and/or an altered sensitivity of brain structures to OEA.
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Affiliation(s)
- A Romano
- Dept. of Physiology and Pharmacology "V. Erspamer", Sapienza Univ. of Rome, 00185 Rome, Italy.
| | - E Karimian Azari
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - B Tempesta
- Dept. of Physiology and Pharmacology "V. Erspamer", Sapienza Univ. of Rome, 00185 Rome, Italy
| | - A Mansouri
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | | | - D Ramachandran
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - T A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty, and Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - G Bedse
- Dept. of Physiology and Pharmacology "V. Erspamer", Sapienza Univ. of Rome, 00185 Rome, Italy
| | - W Langhans
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - S Gaetani
- Dept. of Physiology and Pharmacology "V. Erspamer", Sapienza Univ. of Rome, 00185 Rome, Italy.
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El-Salhy M, Gilja OH, Gundersen D, Hatlebakk JG, Hausken T. Endocrine cells in the ileum of patients with irritable bowel syndrome. World J Gastroenterol 2014; 20:2383-91. [PMID: 24605036 PMCID: PMC3942842 DOI: 10.3748/wjg.v20.i9.2383] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 10/20/2013] [Accepted: 11/18/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To study the ileal endocrine cell types in irritable bowel syndrome (IBS) patients. METHODS Ninety-eight patients with IBS (77 females and 21 males; mean age 35 years, range 18-66 years) were included, of which 35 patients had diarrhea (IBS-D), 31 patients had a mixture of both diarrhea and constipation (IBS-M), and 32 patients had constipation (IBS-C) as the predominant symptoms. The controls were 38 subjects (26 females and 12 males; mean age 40 years, range 18-65 years) who had submitted to colonoscopy for the following reasons: gastrointestinal bleeding, where the source of bleeding was identified as hemorrhoids (n = 24) or angiodysplasia (n = 3), and health worries resulting from a relative being diagnosed with colon carcinoma (n = 11). The patients were asked to complete the: Birmingham IBS symptom questionnaire. Ileal biopsy specimens from all subjects were immunostained using the avidin-biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), enteroglucagon, and somatostatin cells. The cell densities were quantified by computerized image analysis, using Olympus cellSens imaging software. RESULTS The gender and age distributions did not differ significantly between the patients and the controls (P = 0.27 and P = 0.18, respectively). The total score of Birmingham IBS symptom questionnaire was 21 ± 0.8, and the three underlying dimensions: pain, diarrhea, and constipation were 7.2 ± 0.4, 6.6 ± 0.4, and 7.2 ± 0.4, respectively. The density of serotonin cells in the ileum was 40.6 ± 3.6 cells/mm² in the controls, and 11.5 ± 1.2, 10.7 ± 5.6, 10.0 ± 1.9, and 13.9 ± 1.4 cells/mm² in the all IBS patients (IBS-total), IBS-D, IBS-M, and IBS-C patients, respectively. The density in the controls differed significantly from those in the IBS-total, IBS-D, IBS-M, and IBS-C groups (P < 0.0001, P = 0.0001, P = 0.0001, and P < 0.0001, respectively). There was a significant inverse correlation between the serotonin cell density and the pain dimension of Birmingham IBS symptom questionnaire (r = -0.6, P = 0.0002). The density of PYY cells was 26.7 ± 1.6 cells/mm(2) in the controls, and 33.1 ± 1.4, 27.5 ± 1.4, 34.1 ± 2.5, and 41.7 ± 3.1 cells/mm² in the IBS-total, IBS-D, IBS-M, and IBS-C patients, respectively. This density differed significantly between patients with IBS-total and IBS-C and the controls (P = 0.03 and < 0.0001, respectively), but not between controls and, IBS-D, and IBS-M patients (P = 0.8, and P = 0.1, respectively). The density of PYY cells correlated significantly with the degree of constipation as recorded by the Birmingham IBS symptom questionnaire (r = 0.6, P = 0.0002). There were few PP-, enteroglucagon-, and somatostatin-immunoreactive cells in the biopsy material examined, which made it impossible to reliably quantify these cells. CONCLUSION The decrease of ileal serotonin cells is associated with the visceral hypersensitivity seen in all IBS subtypes. The increased density of PYY cells in IBS-C might contribute to the constipation experienced by these patients.
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El-Salhy M, Gundersen D, Gilja OH, Hatlebakk JG, Hausken T. Is irritable bowel syndrome an organic disorder? World J Gastroenterol 2014; 20:384-400. [PMID: 24574708 PMCID: PMC3923014 DOI: 10.3748/wjg.v20.i2.384] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/05/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is generally considered to be functional because there appears to be no associated anatomical defect. Stress and psychological factors are thought to play an important role in IBS. The gut neuroendocrine system (NES), which regulates all functions of the gastrointestinal tract, consists of endocrine cells that are scattered among the epithelial cells of the mucosa, and the enteric nervous system. Although it is capable of operating independently from the central nervous system (CNS), the gut NES is connected to and modulated by the CNS. This review presents evidence for the presence of an anatomical defect in IBS patients, namely in the gastrointestinal endocrine cells. These cells have specialized microvilli that project into the lumen and function as sensors for the luminal content and respond to luminal stimuli by releasing hormones into the lamina propria, which starts a chain reaction that progresses throughout the entire NES. The changes in the gastrointestinal endocrine cells observed in IBS patients are highly consistent with the other abnormalities reported in IBS patients, such as visceral hypersensitivity, dysmotility, and abnormal secretion.
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Newman RE, Downing JA, Thomson PC, Collins CL, Henman DJ, Wilkinson SJ. Insulin secretion, body composition and pig performance are altered by feeding pattern. ANIMAL PRODUCTION SCIENCE 2014. [DOI: 10.1071/an13120] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Three studies investigated the effect of feeding strategy on production performance and endocrine status of growing pigs. For Experiment 1, 20 entire male pigs (70.0 ± 4.6 kg) were allocated randomly to individual pens in one of four climate-controlled rooms. Pigs were fed for 23 days either ad libitum or entrained to feed bi-phasically for two 90-min periods. For Experiment 2, 20 entire male pigs (41.2 ± 3.5 kg) were housed as per Experiment 1. Pigs were fed for 49 days either ad libitum or fed bi-phasically for two 60-min periods. For Experiment 3, 100 female pigs (66.1 ± 3.5 kg) were randomly allocated to individual pens within a commercial piggery and fed for 42 days either ad libitum or bi-phasically for two 60-min periods. Ear vein catheters were inserted into 10 pigs from each group and hourly blood samples were collected for 24 h in Experiments 1 and 2 and for 11 h in Experiment 3. Plasma insulin, non-esterified fatty acid and glucose concentrations were determined in Experiments 1 and 2, and glucose and insulin concentrations in Experiment 3. Feed intake and performance were recorded in all experiments and carcass composition was assessed by computed tomography for Experiment 2. There were no differences in final liveweight between the two treatment groups for all experiments. Pigs fed for two 90-min periods (Experiment 1) showed no difference in feed intake when compared with feeding ad libitum. Pigs in Experiment 2 fed for two 60-min intervals consumed 2.49 kg/pig.day compared with those fed ad libitum that consumed 2.68 kg/day (P = 0.057). In Experiment 3, pigs fed twice daily consumed 2.82 kg/pig.day compared with 2.91 kg/pig.day in ad libitum-fed pigs (P = 0.051). Bi-phasic fed pigs in Experiment 2 had improved (P < 0.05) feed conversion efficiency compared with pigs fed ad libitum. For all experiments, there was no difference in plasma glucose concentrations between the two treatments. In all three experiments, the circulating insulin concentrations for pigs fed ad libitum remained at a constant level throughout the sampling period. However, plasma insulin concentrations for the bi-phasic fed pigs significantly increased ~1 h after both feeding periods during all three experiments. Insulin secretion of pigs fed for two 90-min periods differed from that of pigs fed for two 60-min periods. Plasma insulin concentration increased five-fold following feeding for 60 min, compared with that in pigs fed for 90 min, which increased two-fold. Bi-phasic-fed pigs from Experiment 2 had reduced (P < 0.05) total carcass fat and significantly increased muscle when compared with pigs fed ad libitum. The data showed that feeding pigs at two succinct periods aligned insulin secretion to the time of feeding. Pigs fed for 60 min, unlike those fed for 90-min intervals, had reduced feed intake in comparison to those fed ad libitum. This may suggest that the duration of the feeding bout is important for this response and this may in turn influence both energy balance and the way energy is partitioned.
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Raffa RB, Pergolizzi JV, Taylor R, Decker JF, Patrick JT. Acetaminophen (Paracetamol) Oral Absorption and Clinical Influences. Pain Pract 2013; 14:668-77. [DOI: 10.1111/papr.12130] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 09/15/2013] [Indexed: 12/22/2022]
Affiliation(s)
- Robert B. Raffa
- Department of Pharmaceutical Sciences; Temple University School of Pharmacy; Philadelphia Pennsylvania U.S.A
| | - Joseph V. Pergolizzi
- Department of Medicine; Johns Hopkins University School of Medicine; Baltimore Maryland U.S.A
- Department of Pharmacology; Temple University School of Medicine; Philadelphia Pennsylvania U.S.A
- Department of Anesthesiology; Georgetown University School of Medicine; Washington District of Columbia U.S.A
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Blouet C. Le rôle du noyau du tractus solitaire dans la détection et l’intégration de multiples signaux métaboliques. Med Sci (Paris) 2013; 29:449-52. [DOI: 10.1051/medsci/2013295002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Abstract
Research into the control of energy balance has tended to focus on discrete brain regions, such as the brainstem, medulla, arcuate nucleus of the hypothalamus, and neocortex. Recently, a larger picture has begun to emerge in which the coordinated communication between these areas is proving to be critical to appropriate regulation of metabolism. By serving as a center for such communication, the paraventricular nucleus of the hypothalamus (PVH) is perhaps the most important brain nucleus regulating the physiological response to energetic challenges. Here we review recent advances in the understanding of the circuitry and function of the PVH.
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Affiliation(s)
- Jennifer W. Hill
- Department of Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo Medical Center, Obstetrics-Gynecology, University of Toledo, USA
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Williams KW, Elmquist JK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci 2012; 15:1350-5. [PMID: 23007190 PMCID: PMC3763714 DOI: 10.1038/nn.3217] [Citation(s) in RCA: 311] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Over the past two centuries, prevalent models of energy and glucose homeostasis have emerged from careful anatomical descriptions in tandem with an understanding of cellular physiology. More recent technological advances have culminated in the identification of peripheral and central factors that influence neural circuits regulating metabolism. This Review highlights contributions to our understanding of peripheral and central factors regulating food intake and energy expenditure.
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Affiliation(s)
- Kevin W Williams
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
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Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab 2012; 16:296-309. [PMID: 22902836 PMCID: PMC4862653 DOI: 10.1016/j.cmet.2012.06.015] [Citation(s) in RCA: 356] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 03/20/2012] [Accepted: 06/08/2012] [Indexed: 02/07/2023]
Abstract
This Review highlights the processing and integration performed by hindbrain nuclei, focusing on the inputs received by nucleus tractus solitarius (NTS) neurons. These inputs include vagally mediated gastrointestinal satiation signals, blood-borne energy-related hormonal and nutrient signals, and descending neural signals from the forebrain. We propose that NTS (and hindbrain neurons, more broadly) integrate these multiple energy status signals and issue-output commands controlling the behavioral, autonomic, and endocrine responses that collectively govern energy balance. These hindbrain-mediated controls are neuroanatomically distributed; they involve endemic hindbrain neurons and circuits, hindbrain projections to peripheral circuits, and projections to and from midbrain and forebrain nuclei.
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Affiliation(s)
- Harvey J Grill
- Graduate Group of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Lutz TA. Control of energy homeostasis by amylin. Cell Mol Life Sci 2012; 69:1947-65. [PMID: 22193913 PMCID: PMC11114503 DOI: 10.1007/s00018-011-0905-1] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Revised: 11/13/2011] [Accepted: 12/06/2011] [Indexed: 02/04/2023]
Abstract
Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and increases energy disposal by preventing compensatory decreases of energy expenditure in weight-reduced individuals. The best investigated function of amylin which is cosecreted with insulin is to reduce eating by promoting meal-ending satiation. This effect is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites to mediate amylin action include the nucleus of the solitary tract and the lateral parabrachial nucleus, which convey the neural signal to the lateral hypothalamic area and other hypothalamic nuclei. Amylin may also signal adiposity because plasma levels of amylin are increased in adiposity and because higher amylin concentrations in the brain result in reduced body weight gain and adiposity, while amylin receptor antagonists increase body adiposity. The central mechanisms involved in amylin's effect on energy expenditure are much less known. A series of recent experiments in animals and humans indicate that amylin is a promising option for anti-obesity therapy especially in combination with other hormones. The most extensive dataset is available for the combination therapy of amylin and leptin. Ongoing research focuses on the mechanisms of these interactions.
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Affiliation(s)
- Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Switzerland.
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Cansell C, Denis RGP, Joly-Amado A, Castel J, Luquet S. Arcuate AgRP neurons and the regulation of energy balance. Front Endocrinol (Lausanne) 2012; 3:169. [PMID: 23293630 PMCID: PMC3530831 DOI: 10.3389/fendo.2012.00169] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 12/05/2012] [Indexed: 11/13/2022] Open
Abstract
The arcuate nucleus of the hypothalamus contains at least two populations of neurons that continuously monitor signals reflecting energy status and promote the appropriate behavioral and metabolic responses to changes in energy demand. Activation of neurons making pro-opiomelanocortin (POMC) decreases food intake and increases energy expenditure through activation of G protein-coupled melanocortin receptors via the release of α-melanocyte-stimulating hormone. Until recently, the prevailing idea was that the neighboring neurons [agouti-related protein (AgRP) neurons] co-expressing the orexigenic neuropeptides, AgRP, and neuropeptide Y increase feeding by opposing the anorexigenic actions of the POMC neurons. However, it has now been demonstrated that only AgRP neurons activation - not POMC neurons inhibition - is necessary and sufficient to promote feeding. Projections of AgRP-expressing axons innervate mesolimbic, midbrain, and pontine structures where they regulate feeding and feeding-independent functions such as reward or peripheral nutrient partitioning. AgRP neurons also make gamma aminobutyric acid , which is now thought to mediate many of critical functions of these neurons in a melanocortin-independent manner and on a timescale compatible with neuromodulation.
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Affiliation(s)
- Céline Cansell
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
| | - Raphaël G. P. Denis
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
| | - Aurélie Joly-Amado
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
| | - Julien Castel
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
- Centre National de la Recherche Scientifique EAC 4413Paris, France
| | - Serge Luquet
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
- Centre National de la Recherche Scientifique EAC 4413Paris, France
- *Correspondence: Serge Luquet, Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7, 4 rue Marie-Andrée Lagroua Weill-Hallé, Bâtiment Buffon, Case courrier 7126, 75205 Paris Cedex 13, France. e-mail:
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Gentilcore D, Vanis L, Teng JC, Wishart JM, Buckley JD, Rayner CK, Horowitz M, Jones KL. The oligosaccharide α-cyclodextrin has modest effects to slow gastric emptying and modify the glycaemic response to sucrose in healthy older adults. Br J Nutr 2011; 106:583-587. [PMID: 21554816 DOI: 10.1017/s0007114511000444] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In healthy older subjects, the glycaemic response to carbohydrate-containing meals is dependent on gastric emptying and intestinal absorption; when the latter is slowed, the magnitude of the rise in glucose is attenuated. The oligosaccharide α-cyclodextrin has been reported to diminish the glycaemic response to starch in young adults; this effect has been attributed to the inhibition of pancreatic amylase. We examined the effects of α-cyclodextrin on gastric emptying of, and the glycaemic and insulinaemic responses to, oral sucrose in healthy older subjects; as sucrose is hydrolysed by intestinal disaccharides, any effect(s) of α-cyclodextrin would not be attributable to amylase inhibition. A total of ten subjects (seven males and three females, age 68-76 years) were studied on 2 d. Gastric emptying, blood glucose and serum insulin were measured after ingestion of a 300 ml drink containing 100 g sucrose, labelled with (99m)Tc-sulphur colloid, with or without 10 g α-cyclodextrin. Gastric emptying was slowed slightly by α-cyclodextrin; this effect was evident between 135 and 195 min and was associated with a slight increase (P < 0·05) in distal stomach retention. After α-cyclodextrin, blood glucose was slightly less (P < 0·05) at 60 min, and serum insulin was less (P < 0·0005) at 90 and 120 min. There was no difference in the incremental areas under the curve (iAUC) for blood glucose, but there was a trend for the iAUC for serum insulin to be lower (P = 0·09) after α-cyclodextrin. We conclude that in a dose of 10 g, α-cyclodextrin has modest effects to slow gastric emptying of, and modify the glycaemic and insulinaemic responses to, oral sucrose, probably due to delayed intestinal carbohydrate absorption.
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Affiliation(s)
- Diana Gentilcore
- Discipline of Medicine, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia
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de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab 2011; 301:E187-95. [PMID: 21521717 PMCID: PMC3129833 DOI: 10.1152/ajpendo.00056.2011] [Citation(s) in RCA: 134] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.
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Affiliation(s)
- Guillaume de Lartigue
- Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, USA
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Ghrelin inhibits visceral afferent activation of catecholamine neurons in the solitary tract nucleus. J Neurosci 2011; 31:3484-92. [PMID: 21368060 DOI: 10.1523/jneurosci.3187-10.2011] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Brainstem A2/C2 catecholamine (CA) neurons in the solitary tract nucleus (NTS) are thought to play an important role in the control of food intake and other homeostatic functions. We have previously demonstrated that these neurons, which send extensive projections to brain regions involved in the regulation of appetite, are strongly and directly activated by solitary tract (ST) visceral afferents. Ghrelin, a potent orexigenic peptide released from the stomach, is proposed to act in part through modulating NTS CA neurons but the underlying cellular mechanisms are unknown. Here, we identified CA neurons using transgenic mice that express enhanced green fluorescent protein driven by the tyrosine hydroxylase promoter (TH-EGFP). We then determined how ghrelin modulates TH-EGFP neurons using patch-clamp techniques in a horizontal brain slice preparation. Ghrelin inhibited the frequency of spontaneous glutamate inputs (spontaneous EPSCs) onto TH-EGFP neurons, including cholecystokinin-sensitive neurons, an effect blocked by the GHSR1 antagonist, d-Lys-3-GHRP-6. This resulted in a decrease in the basal firing rate of NTS TH-EGFP neurons, an effect blocked by the glutamate antagonist NBQX. Ghrelin also dose-dependently inhibited the amplitude of ST afferent evoked EPSCs (ST-EPSCs) in TH-EGFP NTS neurons, decreasing the success rate for ST-evoked action potentials. In addition, ghrelin decreased the frequency of mini-EPSCs suggesting its actions are presynaptic to reduce glutamate release. Last, inhibition by ghrelin of the ST-EPSCs was significantly increased by an 18 h fast. These results demonstrate a potential mechanism by which ghrelin inhibits NTS TH neurons through a pathway whose responsiveness is increased during fasting.
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Zeeni N, Nadkarni N, Bell JD, Even PC, Fromentin G, Tome D, Darcel N. Peripherally injected cholecystokinin-induced neuronal activation is modified by dietary composition in mice. Neuroimage 2010; 50:1560-5. [PMID: 20100582 DOI: 10.1016/j.neuroimage.2010.01.065] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Revised: 12/18/2009] [Accepted: 01/18/2010] [Indexed: 11/18/2022] Open
Abstract
The aim of this study was to investigate the effect of long-term nutrient intake on the central response to the anorexigenic gut hormone CCK. C57BL/6 mice were fed one of three diets for 6 weeks: standard high carbohydrate (HC), high fat (HF), or high protein (HP). Assessment of brain response to cholecystokinin (CCK) by manganese-enhanced MRI (MEMRI) showed a reduction in neuronal activity both in an appetite-related area (ventromedial nucleus of the hypothalamus) and areas associated with reward (nucleus accumbens and striatum) regardless of diet. When comparing diet effects, while the HF diet did not induce any change in activity, reductions in MEMRI-associated signal were found in the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) when comparing the HP to the HC diet. In addition, a significant interaction was found between CCK administration and the HF diet, shown by an increased activation in the PVN, which suggests a decrease the inhibiting action of CCK. Our results put forward that the long-term intake of an HP diet leads to a reduction in basal hypothalamic activation while a high-fat diet leads to desensitization to CCK-induced effects in the hypothalamus.
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Affiliation(s)
- N Zeeni
- AgroParisTech, CNRH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, F-75005 Paris, France
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Gautron L, Lee C, Funahashi H, Friedman J, Lee S, Elmquist J. Melanocortin-4 receptor expression in a vago-vagal circuitry involved in postprandial functions. J Comp Neurol 2010; 518:6-24. [PMID: 19882715 DOI: 10.1002/cne.22221] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Vagal afferents regulate energy balance by providing a link between the brain and postprandial signals originating from the gut. In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the nodose ganglion, where the cell bodies of vagal sensory afferents reside. By using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found GFP expression in approximately one-third of nodose ganglion neurons. By using immunohistochemistry combined with in situ hybridization, we also demonstrated that approximately 20% of GFP-positive neurons coexpressed cholecystokinin receptor A. In addition, we found that the GFP is transported to peripheral tissues by both vagal sensory afferents and motor efferents, which allowed us to assess the sites innervated by MC4R-GFP neurons. GFP-positive efferents that co-expressed choline acetyltransferase specifically terminated in the hepatic artery and the myenteric plexus of the stomach and duodenum. In contrast, GFP-positive afferents that did not express cholinergic or sympathetic markers terminated in the submucosal plexus and mucosa of the duodenum. Retrograde tracing experiments confirmed the innervation of the duodenum by GFP-positive neurons located in the nodose ganglion. Our findings support the hypothesis that MC4R signaling in vagal afferents may modulate the activity of fibers sensitive to satiety signals such as cholecystokinin, and that MC4R signaling in vagal efferents may contribute to the control of the liver and gastrointestinal tract.
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Affiliation(s)
- Laurent Gautron
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9077, USA
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Blouet C, Schwartz GJ. Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 2009; 209:1-12. [PMID: 20035790 DOI: 10.1016/j.bbr.2009.12.024] [Citation(s) in RCA: 220] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Accepted: 12/16/2009] [Indexed: 12/15/2022]
Abstract
The hypothalamus is a center of convergence and integration of multiple nutrient-related signals. It can sense changes in circulating adiposity hormones, gastric hormones and nutrients, and receives neuroanatomical projections from other nutrient sensors, mainly within the brainstem. The hypothalamus also integrates these signals with various cognitive forebrain-descending information and reward/motivation-related signals coming from the midbrain-dopamine system, to coordinate neuroendocrine, behavioral and metabolic effectors of energy balance. Some of the key nutrient-sensing hypothalamic neurons have been identified in the arcuate, the ventro-medial and the lateral nuclei of the hypothalamus, and the molecular mechanisms underlying intracellular integration of nutrient-related signals in these neurons are currently under intensive investigation. However, little is known about the neural pathways downstream from hypothalamic nutrient sensors, and how they drive effectors of energy homeostasis under physiological conditions. This manuscript will review recent progress from molecular, genetic and neurophysiological studies that identify and characterize the critical intracellular signalling pathways and neurocircuits involved in determining hypothalamic nutrient detection, and link these circuits to behavioral and metabolic effectors of energy balance. We will provide a critical analysis of current data to identify ongoing challenges for future research in this field.
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Affiliation(s)
- Clémence Blouet
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
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Shu D, Qin J, Ma X, Xue C, Liu J, Bi Y, Cao Y. Active or passive immunisation against cholecystokinin-33 stimulates growth of pigs. FOOD AGR IMMUNOL 2009. [DOI: 10.1080/09540100903365845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Mediobasal hypothalamic leucine sensing regulates food intake through activation of a hypothalamus-brainstem circuit. J Neurosci 2009; 29:8302-11. [PMID: 19571121 DOI: 10.1523/jneurosci.1668-09.2009] [Citation(s) in RCA: 170] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
In response to nutrient stimuli, the mediobasal hypothalamus (MBH) drives multiple neuroendocrine and behavioral mechanisms to regulate energy balance. While central leucine reduces food intake and body weight, the specific neuroanatomical sites of leucine sensing, downstream neural substrates, and neurochemical effectors involved in this regulation remain largely unknown. Here we demonstrate that MBH leucine engages a neural energy regulatory circuit by stimulating POMC (proopiomelanocortin) neurons of the MBH, oxytocin neurons of the paraventricular hypothalamus, and neurons within the brainstem nucleus of the solitary tract to acutely suppress food intake by reducing meal size. We identify central p70 S6 kinase and Erk1/2 pathways as intracellular effectors required for this response. Activation of endogenous leucine intracellular metabolism produced longer-term reductions in meal number. Our data identify a novel, specific hypothalamus-brainstem circuit that links amino acid availability and nutrient sensing to the control of food intake.
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Nefti W, Chaumontet C, Fromentin G, Tomé D, Darcel N. A high-fat diet attenuates the central response to within-meal satiation signals and modifies the receptor expression of vagal afferents in mice. Am J Physiol Regul Integr Comp Physiol 2009; 296:R1681-6. [DOI: 10.1152/ajpregu.90733.2008] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
During digestion, macronutrients are sensed within the small intestine. This sensory process is dependent upon the action of gut mediators, such as cholecystokinin (CCK) or serotonin (5-HT), on vagal afferents that, in turn, convey peripheral information to the brain to influence the control of food intake. Recent studies have suggested that dietary conditions alter vagal sensitivity to CCK and 5-HT. This phenomenon may be of importance to the onset of eating disorders. The aim of the present study was thus to investigate the effects of subjecting mice to 15 days of either an HF diet (30% fat, 54% carbohydrate) or an NF diet (10% fat, 74% carbohydrate) on 1) daily and short-term food intake, 2) vagal sensitivity to peripheral anorectic factors and macronutrient loads, and 3) vagal afferent neuron receptor expression. The results indicated that compared with an NF diet, and while increasing food intake and body weight gain, an HF diet altered the short-term response to CCK-8 and intragastric macronutrient loads, while decreasing vagal activation by CCK-8 and modifying the receptor expression of vagal neurons. These findings, therefore, suggest that dietary intervention effect on food intake could be linked to changes in vagal afferent receptor profiles.
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Signals that link energy to reproduction: Gastric fill, bulk intake, or caloric intake? Physiol Behav 2009; 96:540-7. [DOI: 10.1016/j.physbeh.2008.12.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2008] [Revised: 12/02/2008] [Accepted: 12/10/2008] [Indexed: 11/21/2022]
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Claessens M, van Baak MA, Monsheimer S, Saris WHM. The effect of a low-fat, high-protein or high-carbohydrate ad libitum diet on weight loss maintenance and metabolic risk factors. Int J Obes (Lond) 2009; 33:296-304. [PMID: 19153580 DOI: 10.1038/ijo.2008.278] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND High-protein (HP) diets are often advocated for weight reduction and weight loss maintenance. OBJECTIVE The aim was to compare the effect of low-fat, high-carbohydrate (HC) and low-fat, HP ad libitum diets on weight maintenance after weight loss induced by a very low-calorie diet, and on metabolic and cardiovascular risk factors in healthy obese subjects. DESIGN Forty-eight subjects completed the study that consisted of an energy restriction period of 5-6 weeks followed by a weight maintenance period of 12 weeks. During weight maintenance subjects received maltodextrin (HC group) or protein (HP group) (casein (HPC subgroup) or whey (HPW subgroup)) supplements (2 x 25 g per day), respectively and consumed a low-fat diet. RESULTS Subjects in the HP diet group showed significantly better weight maintenance after weight loss (2.3 kg difference, P=0.04) and fat mass reduction (2.2 kg difference, P=0.02) than subjects in the HC group. Triglyceride (0.6 mM difference, P=0.01) and glucagon (9.6 pg ml(-1) difference, P=0.02) concentrations increased more in the HC diet group, while glucose (0.3 mM difference, P=0.02) concentration increased more in the HP diet group. Changes in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, insulin, HOMAir index, HbA1c, leptin and adiponectin concentrations did not differ between the diets. No differences were found between the casein- or whey-supplemented HP groups. CONCLUSIONS These results show that low-fat, high-casein or whey protein weight maintenance diets are more effective for weight control than low-fat, HC diets and do not adversely affect metabolic and cardiovascular risk factors in weight-reduced moderately obese subjects without metabolic or cardiovascular complications.
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Affiliation(s)
- M Claessens
- Department of Human Biology, Nutrition and Toxicology Research institute Maastricht, Maastricht University, Maastricht, The Netherlands
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The effect of sham feeding on neurocardiac regulation in healthy human volunteers. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2008; 21:721-6. [PMID: 18026575 DOI: 10.1155/2007/891374] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Distension and electrical stimuli in the esophagus alter heart rate variability (HRV) consistent with activation of vagal afferent and efferent pathways. Sham feeding stimulates gastric acid secretion by means of vagal efferent pathways. It is not known, however, whether activation of vagal efferent pathways is organ- or stimulus-specific. OBJECTIVE To test the hypothesis that sham feeding increases the high frequency (HF) component of HRV, indicating increased neurocardiac vagal activity in association with the known, vagally mediated, increase in gastric acid secretion. METHODS Continuous electrocardiography recordings were obtained in 12 healthy, semirecumbent subjects during consecutive 45 min baseline, 20 min sham feeding (standard hamburger meal) and 45 min recovery periods. The R-R intervals and beat-to-beat heart rate signal were determined from digitized electrocardiography recordings; power spectra were computed from the heart rate signal to determine sympathetic (low frequency [LF]) and vagal (HF) components of HRV. RESULTS Heart rate increased during sham feeding (median 70.8 beats/min, 95% CI 66.0 to 77.6; P<0.001), compared with baseline (63.6, 95% CI 60.8 to 70.0) and returned to baseline levels within 45 min. Sham feeding increased the LF to HF area ratio (median: 1.55, 95% C.I 1.28 to 1.77; P<0.021, compared with baseline (1.29, 95% CI 1.05 to 1.46); this increase in LF to HF area ratio was associated with a decrease in the HF component of HRV. CONCLUSIONS Sham feeding produces a reversible increase in heart rate that is attributable to a decrease in neurocardiac parasympathetic activity despite its known ability to increase vagally mediated gastric acid secretion. These findings suggest that concurrent changes in cardiac and gastric function are modulated independently by vagal efferent fibres and that vagally mediated changes in organ function are stimulus- and organ-specific.
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Visceral afferents directly activate catecholamine neurons in the solitary tract nucleus. J Neurosci 2008; 27:13292-302. [PMID: 18045923 DOI: 10.1523/jneurosci.3502-07.2007] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Brainstem A2/C2 neurons are catecholamine (CA) neurons within the solitary tract nucleus (NTS) that influence many homeostatic functions, including cardiovascular reflexes, food intake, and stress. Because NTS is a major interface between sensory visceral afferents and the CNS, NTS CA neurons are ideally suited to coordinate complex responses by their projections to multiple brain regions. To test how NTS CA neurons process visceral afferent information carried by solitary tract (ST) afferents, we identified CA neurons using transgenic mice expressing TH-EGFP (enhanced green fluorescent protein under the control of the tyrosine hydroxylase promoter) and recorded synaptic responses to ST activation in horizontal slices. ST shocks evoked large-amplitude, short-latency, glutamatergic EPSCs (ST-EPSCs) in 90% of NTS CA neurons. Within neurons, ST-EPSCs had constant latency, rarely failed, and depressed substantially at high ST frequencies, indicating that NTS CA neurons receive direct monosynaptic connections from afferent terminals. NTS CA neurons received direct ST inputs from only one or two afferent fibers, with one-half also receiving smaller amplitude indirect inputs. Up to 90% of ST shocks evoked action potentials in NTS CA neurons. However, transmission of sensory afferent information through NTS CA neurons critically depended on the expression of an A-type potassium current (I(KA)), which when active attenuated ST-activated action potentials to a 37% success rate. The satiety peptide, cholecystokinin, presynaptically facilitated glutamate transmission in one-half of NTS CA neurons. Thus, NTS CA neurons are directly driven by visceral afferents with output being modulated by presynaptic peptide receptors and postsynaptic potassium channels.
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Paulino G, Darcel N, Tome D, Raybould H. Adaptation of lipid-induced satiation is not dependent on caloric density in rats. Physiol Behav 2007; 93:930-6. [PMID: 18234246 DOI: 10.1016/j.physbeh.2007.12.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2007] [Revised: 12/13/2007] [Accepted: 12/19/2007] [Indexed: 01/15/2023]
Abstract
UNLABELLED Food intake is modulated by ingestive (gastrointestinal) and post-ingestive signals; ingested fat is potent to produce short-term satiety (satiation) but this can be modified by long-term ingestion of a high fat diet. AIM Determine whether altered lipid-induced satiation is dependent on the fat content of the diet, rather than increased caloric density or changes in adiposity. METHODS Initial experiments determined the differences in the microstructure of meal patterns in rats fed a high fat diet (HF: 38% fat kcal) and in rats pair-fed an isocaloric, isonitrogenous low fat diet (LF: 10% fat kcal) and changes in meal patterns measured after long-term maintenance on the HF diet. RESULTS Rats fed the HF diet had a significant 50% increase in meal frequency compared to rats fed the LF diet; in addition, there was a significant reduction in meal size (32%) and inter meal interval (38%) consistent with induction of satiation. After 8 weeks on the HF diet, these parameters tend to approach those of rats maintained on the LF diet. There was a significant 56% decrease in the activation of neurons in the NTS in response to intragastric gavage of lipid in rats maintained for 8 weeks on the HF compared to LF diet. CONCLUSION Dietary fat alters meal patterns consistent with induction of a short-term satiety signal. This signal is attenuated with long-term exposure to dietary lipid, in the absence of ingestion of additional calories or changes in body weight. This adaptation of short-term satiety might contribute to diet-induced obesity.
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Affiliation(s)
- G Paulino
- Department Anatomy, Physiology and Cell Biology, UC Davis School of Veterinary Medicine, CA, USA
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De-stabilization of the positive vago-vagal reflex in bulimia nervosa. Physiol Behav 2007; 94:136-53. [PMID: 18191425 DOI: 10.1016/j.physbeh.2007.11.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2007] [Accepted: 11/15/2007] [Indexed: 01/16/2023]
Abstract
Bulimia nervosa is characterized by consuming large amounts of food over a defined period with a loss of control over the eating. This is followed by a compensatory behavior directed at eliminating the consumed calories, usually vomiting. Current treatments include antidepressants and/or behavioral therapies. Consensus exists that these treatments are not very effective and are associated with high relapse rates. We review evidence from literature and present original data to evaluate the hypothesis that bulimia involves alterations in vago-vagal function. Evidence in support of this include (1) laboratory studies consistently illustrate deficits in meal size, meal termination, and satiety in bulimia; (2) basic science studies indicate that meal size and satiation are under vagal influences; (3) anatomical, behavioral and physiological data suggest that achieving satiety and the initiation of emesis involve common neural substrates; (4) abnormal vagal and vago-vagal reflexive functions extend to non-eating activational stimuli; and (5) studies from our laboratory modulating vagal activation have shown significant effects on binge/vomit frequencies and suggest a return of normal satiation. We propose a model for the pathophysiology of bulimia based upon de-stabilization of a bi-stable positive vago-vagal feedback loop. This model is not meant to be complete, but rather to stimulate anatomical, psychobiological, and translational neuroscience experiments aimed at elucidating the pathophysiology of bulimia and developing novel treatment strategies.
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Williams DL, Schwartz MW, Bastian LS, Blevins JE, Baskin DG. Immunocytochemistry and laser capture microdissection for real-time quantitative PCR identify hindbrain neurons activated by interaction between leptin and cholecystokinin. J Histochem Cytochem 2007; 56:285-93. [PMID: 18040081 DOI: 10.1369/jhc.7a7331.2007] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Current evidence suggests that leptin reduces food intake in part by enhancing the hindbrain neuronal response to meal-related gastrointestinal signals, including cholecystokinin (CCK), but the phenotypes of the relevant cells are not known. To identify neurons that participate in this interaction in the rat nucleus of the solitary tract (NTS), we induced c-Fos gene expression in NTS neurons with leptin and CCK. We focused on NTS catecholamine neurons because these cells have been implicated in the feeding response to CCK. Hindbrain sections from rats that received CCK with or without leptin pretreatment were immunostained for c-Fos and tyrosine hydroxylase (TH) by a double immunofluorescence procedure. Leptin pretreatment increased the number of NTS cells expressing c-Fos-like immunoreactivity (cFLI) 3-fold relative to CCK alone, but the number of TH-positive cells with cFLI was increased 6-fold. Next, cells detected by immunofluorescence for TH were collected by laser capture microdissection and pooled for real-time quantitative PCR of c-Fos mRNA. Here, neither le0ptin nor CCK alone affected the relative amount of mRNA in the TH cell-enriched samples, but leptin plus CCK substantially increased c-Fos mRNA content. These histochemical findings identify hindbrain catecholamine cells as potential mediators of the interaction between leptin and CCK.
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Affiliation(s)
- Diana L Williams
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
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Viard E, Zheng Z, Wan S, Travagli RA. Vagally mediated, nonparacrine effects of cholecystokinin-8s on rat pancreatic exocrine secretion. Am J Physiol Gastrointest Liver Physiol 2007; 293:G493-500. [PMID: 17569741 DOI: 10.1152/ajpgi.00118.2007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cholecystokinin (CCK) has been proposed to act in a vagally dependent manner to increase pancreatic exocrine secretion via actions exclusively at peripheral vagal afferent fibers. Recent evidence, however, suggests the CCK-8s may also affect brain stem structures directly. We used an in vivo preparation with the aims of 1) investigating whether the actions of intraduodenal casein perfusion to increase pancreatic protein secretion also involved direct actions of CCK at the level of the brain stem and, if so, 2) determining whether, in the absence of vagal afferent inputs, CCK-8s applied to the dorsal vagal complex (DVC) can also modulate pancreatic exocrine secretion (PES). Sprague-Dawley rats (250-400 g) were anesthetized and the common bile-pancreatic duct was cannulated to collect PES. Both vagal deafferentation and pretreatment with the CCK-A antagonist lorglumide on the floor of the fourth ventricle decreased the casein-induced increase in PES output. CCK-8s microinjection (450 pmol) in the DVC significantly increased PES; the increase was larger when CCK-8s was injected in the left side of the DVC. Protein secretion returned to baseline levels within 30 min. Microinjection of CCK-8s increased PES (although to a lower extent) also in rats that underwent complete vagal deafferentation. These data indicate that, as well as activating peripheral vagal afferents, CCK-8s increases pancreatic exocrine secretion via an action in the DVC. Our data suggest that the CCK-8s-induced increases in PES are due mainly to a paracrine effect of CCK; however, a relevant portion of the effects of CCK is due also to an effect of the peptide on brain stem vagal circuits.
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Affiliation(s)
- Eddy Viard
- Department of Neuroscience, Pennington Biomedical Research Center-Louisiana State University System, 6400 Perkins Rd., Baton Rouge, LA 70808, USA
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Wan S, Coleman FH, Travagli RA. Cholecystokinin-8s excites identified rat pancreatic-projecting vagal motoneurons. Am J Physiol Gastrointest Liver Physiol 2007; 293:G484-92. [PMID: 17569742 DOI: 10.1152/ajpgi.00116.2007] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
It is known that cholecystokinin (CCK) acts in a paracrine fashion to increase pancreatic exocrine secretion via vagal circuits. Recent evidence, however, suggests that CCK-8s actions are not restricted to afferent vagal fibers, but also affect brain stem structures directly. Within the brain stem, preganglionic neurons of the dorsal motor nucleus of the vagus (DMV) send efferent fibers to subdiaphragmatic viscera, including the pancreas. Our aims were to investigate whether DMV neurons responded to exogenously applied CCK-8s and, if so, the mechanism of action. Using whole cell patch-clamp recordings we show that perfusion with CCK-8s induced a concentration-dependent excitation in approximately 60% of identified pancreas-projecting DMV neurons. The depolarization was significantly reduced by tetrodotoxin, suggesting both direct (on the DMV membrane) and indirect (on local synaptic circuits) effects. Indeed, CCK-8s increased the frequency of miniature excitatory currents onto DMV neurons. The CCK-A antagonist, lorglumide, prevented the CCK-8s-mediated excitation whereas the CCK-B preferring agonist, CCK-nonsulfated, had no effect, suggesting the involvement of CCK-A receptors only. In voltage clamp, the CCK-8s-induced inward current reversed at -106 +/- 3 mV and the input resistance increased by 150 +/- 15%, suggesting an effect mediated by the closure of a potassium conductance. Indeed, CCK-8s reduced both the amplitude and the time constant of decay of a calcium-dependent potassium conductance. When tested with pancreatic polypeptide (which reduces pancreatic exocrine secretion), cells that responded to CCK-8s with an excitation were, instead, inhibited by pancreatic polypeptide. These data indicate that CCK-8s may control pancreas-exocrine secretion also via an effect on pancreas-projecting DMV neurons.
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Affiliation(s)
- Shuxia Wan
- Department of Neuroscience, Pennington Biomedical Research Center-Louisiana State University System, 6400 Perkins Rd., Baton Rouge, LA 70808, USA
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Zanutto BS, Staddon JER. Bang-bang control of feeding: role of hypothalamic and satiety signals. PLoS Comput Biol 2007; 3:e97. [PMID: 17530919 PMCID: PMC1876490 DOI: 10.1371/journal.pcbi.0030097] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2006] [Accepted: 04/17/2007] [Indexed: 01/09/2023] Open
Abstract
Rats, people, and many other omnivores eat in meals rather than continuously. We show by experimental test that eating in meals is regulated by a simple bang-bang control system, an idea foreshadowed by Le Magnen and many others, shown by us to account for a wide range of behavioral data, but never explicitly tested or tied to neurophysiological facts. The hypothesis is simply that the tendency to eat rises with time at a rate determined by satiety signals. When these signals fall below a set point, eating begins, in on-off fashion. The delayed sequelae of eating increment the satiety signals, which eventually turn eating off. Thus, under free conditions, the organism eats in bouts separated by noneating activities. We report an experiment with rats to test novel predictions about meal patterns that are not explained by existing homeostatic approaches. Access to food was systematically but unpredictably interrupted just as the animal tried to start a new meal. A simple bang-bang model fits the resulting meal-pattern data well, and its elements can be identified with neurophysiological processes. Hypothalamic inputs can provide the set point for longer-term regulation carried out by a comparator in the hindbrain. Delayed gustatory and gastrointestinal aftereffects of eating act via the nucleus of the solitary tract and other hindbrain regions as neural feedback governing short-term regulation. In this way, the model forges real links between a functioning feedback mechanism, neuro-hormonal data, and both short-term (meals) and long-term (eating-rate regulation) behavioral data.
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Affiliation(s)
- B Silvano Zanutto
- Instituto de Ingeniería Biomédica-Universidad de Buenos Aires, Buenos Aires, Argentina.
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Baptista V, Browning KN, Travagli RA. Effects of cholecystokinin-8s in the nucleus tractus solitarius of vagally deafferented rats. Am J Physiol Regul Integr Comp Physiol 2006; 292:R1092-100. [PMID: 17122331 PMCID: PMC3062489 DOI: 10.1152/ajpregu.00517.2006] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We have shown recently that cholecystokinin octapeptide (CCK-8s) increases glutamate release from nerve terminals onto neurons of the nucleus tractus solitarius pars centralis (cNTS). The effects of CCK on gastrointestinal-related functions have, however, been attributed almost exclusively to its paracrine action on vagal afferent fibers. Because it has been reported that systemic or perivagal capsaicin pretreatment abolishes the effects of CCK, the aim of the present work was to investigate the response of cNTS neurons to CCK-8s in vagally deafferented rats. In surgically deafferented rats, intraperitoneal administration of 1 or 3 mug/kg CCK-8s increased c-Fos expression in cNTS neurons (139 and 251% of control, respectively), suggesting that CCK-8s' effects are partially independent of vagal afferent fibers. Using whole cell patch-clamp techniques in thin brain stem slices, we observed that CCK-8s increased the frequency of spontaneous and miniature excitatory postsynaptic currents in 43% of the cNTS neurons via a presynaptic mechanism. In slices from deafferented rats, the percentage of cNTS neurons receiving glutamatergic inputs responding to CCK-8s decreased by approximately 50%, further suggesting that central terminals of vagal afferent fibers are not the sole site for the action of CCK-8s in the brain stem. Taken together, our data suggest that the sites of action of CCK-8s include the brain stem, and in cNTS, the actions of CCK-8s are not restricted to vagal central terminals but that nonvagal synapses are also involved.
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Affiliation(s)
- V Baptista
- Department of Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA
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